Clinical studies have shown that the elderly are susceptible to multiple disease processes including cancer, autoimmunity and infections, implying that aging leads to aberrant immune function. However, the mechanisms by which aging impairs immunity remain obscure. Due to the rapid expansion of the elderly subpopulation in Western countries, and the heavy burden such growth will pose on our health-care resources, there is an urgent need both for more research into immunity and aging and for the development of more effective therapies for treating the elderly. Our preliminary data demonstrates that primary T cell dependent immunity is impaired in aged vs. young T cells due to defective up-regulation of the ICOS costimulatory receptor. Hence, this proposal will test the hypothesis that restoring costimulatory receptor up-regulation during a primary immune response will enhance immune memory generation in aged hosts and restore protective immune memory. Specifically, we will examine if defective up-regulation of costimulatory receptors is responsible for impaired primary anti-viral immunity in aged murine hosts (aim 1). We will then investigate if adjuvant therapy will restore the up-regulation of costimulatory receptors on viral specific T cells and rescue the primary immmune response in the aged host (aim 2). Finally, we will examine if recovered primary immunity leads to preserved immune memory responses in the aged host (aim 3). As a result, this proposal will provide essential mechanistic information as to whether immune memory can be enhanced in the aged host and will help accelerate clinically relevant protocols for enhancing the efficacy of vaccinations in the elderly. Dr. Goldstein is a highly promising physician scientist who has already published in high-impact journals in transplant immunology. He has switched his focus to immunosenescence and is committed to exploring the basic mechanisms of aging and immunity. Yale University has a long and outstanding record in fostering the careers of young physician scientists. The additional mentored support offered by this RFA is critical for Dr. Goldstein to develop expertise in the biology of aging and how it relates to immunosenescence, ensuring that Dr. Goldstein will become a leading independent physician scientist in this area. [unreadable] [unreadable] [unreadable]